Project Summary This is a supplement to the parent R01 award 5R01AG027060-10: FOXO3 Genotype, InflammAging, Cardiovascular Disease, and Dementia. Kuakini Hawaii Lifespan Study III. The parent R01 study proposed to utilize the Kuakini Honolulu Heart Program/Kuakini Honolulu-Asia Aging Study (Kuakini HHP/Kuakini HAAS) cohort. The Kuakini HHP study began in 1965. AIM 1. CONDUCT a prospective study of FOXO3 genotype on incident disease and mortality across most of the adult lifespan. Hypothesis: FOXO3 enhances longevity over the adult lifespan principally through protection against vascular disease. AIM 2. TEST whether carriers of the longevity-associated FOXO3 allele have a protective anti- inflammatory serum profile. Hypothesis: FOXO3 reduces mortality through a cytokine-mediated anti-inflammatory pathway. AIM 3. TEST whether FOXO3 genotype influences cognitive aging, AD and VCID. Hypothesis: Gene variants that promote longevity may also promote healthy brain aging, including better cognitive function, less brain pathology on autopsy and lower rates of incident AD and VCID. Inflammation may be a mediating factor. The parent award was in response to PA-16-160: Research Project Grant (Parent R01). As such, the focus was not on new data collection. A clinical exam and bio-specimen collection on the oldest members of the cohort (centenarians) would, however, be of exceptional value. This would enable the world's only truly longitudinal centenarian study that has data prospectively collected over several prior decades. This would optimize the ability of our statistical models to assess how the FOXO3 gene influences the ability to live to exceptional old age including the potential role of inflammaging on longevity and healthy aging, particularly cognitive aging. The most valuable data would be from the remaining members of this exceptional longitudinal human cohort study. Therefore, the AIM of this supplement is to conduct an unprecedented 55-year follow-up clinical examination on the ~50 remaining participants of the Kuakini HHP/Kuakini HAAS study (all will be centenarians as of 1/1/2020) and measure an additional 800 cytokines to extend the cytokine follow-up to over a multi-decade follow-up. This addresses the need to urgently examine the oldest surviving members of our exceptionally valuable cohort. Of major importance to human aging research, this supplement will also provide a unique resource that does not currently exist, for studies of healthy human aging. It will provide clinical data on enough centenarians to enable the first longitudinal study of centenarians, conducted from mid-life.